Follicular Lymphoma (FL) represents the second most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de-novo diagnoses (Swerdlow et al., 2008). Despite its indolent nature and progress in the development of new therapeutic regimens FL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for disease development and that can be targeted therapeutically. Thus, identifying new oncogenes and tumor suppressors and defining their normal cellular functions and role in lymphomagenesis remains a major research imperative in order to develop targeted, highly specific therapies. Using next-generation whole-exome sequencing analysis and high-density single nucleotide polymorphism (SNP) array analysis we have shown that over 40% of FL cases are associated with structural alterations inactivating CREBBP (CBP) and EP300 (p300), two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. We have demonstrated that CBP/p300 inactivation leads to specific defects in the acetylation-mediated inactivation of the BCL6 onco-protein and activation of the p53 tumor suppressor, therefore suggesting one possible mechanism by which these lesions may contribute to cell transformation (Pasqualucci et al., Nature, in press). Based on these results, the general objective of this project is to elucidate the role of CBP and p300 in FL pathogenesis and to establish pre-clinical models for their therapeutic targeting. The following Specific Aims will be pursued: Aim 1. Identify the full spectrum of genetic and epigenetic lesions affecting CBP/p300 in FL. Aim 2. Identify consequences of p300 inactivation in FL by identifying genes regulated by p300 and affected by its inactivation. Aim 3. Elucidate the role of CBP and p300 inactivation in FL pathogenesis in vivo by constructing mice in which CBP or p300 inactivation in B cells is combined deregulation of BCL2, thus mimicking human FL PUBLIC HEALTH RELEVANCE: The results of this project will provide direct insights into the pathogenesis of Follicular Lymphoma, pre-clinical models for this disease, and may identify FL cases for specific targeted therapy using available drugs.